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BIOLOGY OF DISEASES

BIOLOGY OF DISEASES. Skin diseases. Topics. Epidermal Stem Cells Skin cancer Basal cell carcinoma Squamous cell carcinoma Melanoma Psoriasis. Epidermal Stem Cells. Epidermal stem cells are a subpopulation of keratinocytes

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BIOLOGY OF DISEASES

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  1. BIOLOGY OF DISEASES • Skin diseases

  2. Topics • Epidermal Stem Cells • Skin cancer • Basal cell carcinoma • Squamous cell carcinoma • Melanoma • Psoriasis

  3. Epidermal Stem Cells • Epidermal stem cells are a subpopulation of keratinocytes • Epidermal stem cells give rise to interfollicular epidermis, hair follicles and sebaceous glands • Sweat glands are derived from the epidermis during embryonic development but is is not known whether epidermal stem cells contribute to this differentiation pathway during postnatal life.

  4. Properties of Stem Cells • Not terminally differentiated • Can divide without limit (at least for the lifetime) • When a stem cell divides, each daughter cell has a choice: remain as a stem cell or embark on a course that commits to differentiation • Self-maintenance of stem cell population • Often pluripotent differentiation potential

  5. Transit amplifying cells

  6. Model of epidermal cell lineages

  7. Maintenance of stem cell compartment • Divisional asymmetry • Population asymmetry • Epidermal stem cells form clusters • Locations: upper hair follicle (bulge) and patches of basal keratinocytes at the tips of dermal papillae (between rete ridges) • Stem cell niche

  8. Stem cell niche

  9. Stem Cell Research • Problem: no definite cell surface marker to distinguish pure populations of epidermal stem cells (compare to haematopoietic stem cells). • Indirect methods utilised

  10. Clone forming ability of individual keratinocytes • Only stem cells have unlimited potential for cell divisions. • When keratinocytes are cultured in low density only stem cells give rise to large colonies • Transfection and viral transduction can be used to manipulate cells in culture

  11. Stem cells are slowly cycling in vivo

  12. Stem cell fate can be studied invivo using transgenic mice

  13. Biomedical applications for epidermal stem cells • Wound healing • Gene therapy • Implications in carcinogenesis

  14. Skin Cancer • Mouse 2-stage skin carcinogenesis => tumour growth can be promoted even 1 year after exposure to carcinogen. • Mutated differentiated cells are shed off from the surface of the skin but mutated stem cells and their stem cell daughters remain in the skin and can acquire further mutational hits

  15. 2-stage skin carcinogenesis • Mutations are caused by applying a mutagen ( for example DMBA) to shaved back skin • Tumour growth is promoted by repeated applications of TPA over several weeks • Multiple benign papillomas, some of them convert to malignant carcinomas. • When applied to transgenic or knock-out mice, 2-stage model gives information on roles of individual proteins in carcinogenesis

  16. Skin cancer • Basal Cell Carcinoma and Squamous Cell Carcinoma are of keratinocyte origin • Melanoma originates from melanocytes

  17. Ultraviolet light is carcinogenic

  18. Sunburn

  19. UV light is mutagen

  20. DNA-Repair mechanisms protect cells from mutagens • Excision repair mechanism can cut out thymine dimers • Xeroderma Pigmentosum, a rare inherited disease. Affected individual lack excision repair and are extremely prone to skin cancer.

  21. Basal Cell Carcinoma

  22. Basal Cell Carcinoma • Basal cell carcinoma is hardly ever invasive and can be completely cured by surgery

  23. Basal Cell Carcinoma

  24. Inherited BCC Naevus

  25. Actinic Keratoses

  26. Squamous Cell Carcinoma

  27. Squamous Cell Carcinoma

  28. Malignant melanoma

  29. Sunburn and melanoma

  30. Melanocytes

  31. Melanoma - staging is important prognostic tool

  32. Familial melanoma - mutations in p16 INK tumour suppressor gene

  33. Invasion and metastasis • Cytoskeleton • Adhesion • Cell-cell • Cell-matrix • Signalling proteins • Rho family • Tumour microenvironment • Matrix Metalloproteinases

  34. ECM Turnover - MMPs • Matrix metalloproteinases are enzymes that cleave components of ECM • Over 20 different enzymes with differenrt specificities. • Common theme: expressed as an inactive proenzyme • Also other substrates than ECM proteins • TIMPs = tissue inhibitors of MMPs

  35. Experimental Therapies for Melanoma • Immunotherapy - Tumour vaccines • Some promising results • Inhibitors of MMPs • Against invasion and angiogenesis • Early results in human trials (many different tumour types) disappointing

  36. Psoriasis - a disease of immune cells and keratinocytes

  37. Psoriasis has a genetic component

  38. Chicken or Egg

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